Opioids and cannabinoids affect not only the nervous, but also the immune system in humans and rodents. Mu, kappa, and delta opioid receptors and CB1 and CB2 cannabinoid receptors have been demonstrated in the immune system. In addition, in rodents, products of the immune system, such as cytokines, have been shown to alter neural function and to modify the effects of opioids on body temperature and analgesia. Chemokines, a subclass of cytokines, are produced by microglia in the brain. In human peripheral blood mononuclear cells, it has been shown that there is an interaction between opioid receptors and chemokine receptors, both being G-protein coupled, seven transmembrane receptors. Selected ligands for each class of receptor can cross-desensitize the other by cross-phosphorylation. Our preliminary results using transfected cell lines support this conclusion as do our recent novel and very exciting results showing that chemokines injected into rat brain PAG block opioid- induced analgesia. The findings suggest the chemokines may alter opioid function in the brain. We have also found super- and sub- additive effects of opioid receptor-selective ligands (mu and delta2) on immune cell function, as well as similar effects between opioids and cannabinoids. Taken together, these results suggest that the opioid, cannabinoid, and chemokine systems interact in the immune system and in the nervous system. It is the purpose of the proposed studies to document the nature of the interactions among these three classes of ligands and their receptors in both the immune and nervous systems. Specifically, we propose to 1) determine the interactions that occur among the classical opioid receptor types and between opioids and cannabinoids in the immune system of mice; 2) determine the cross-regulation of opioid, cannabinoid, and chemokine receptor function in primary human cells and transfected cell lines, and the effect of combinations of these classes of ligands on HIV replication; and 3) examine the effects of Chemokines given supraspinally to rats and mice on morphine- and cannabinoid- mediated analgesia and hypothermia. These studies will explore basic interactions between abused drugs and immune function, and between products of the immune system and these drugs on nervous system function, whether the drugs are used therapeutically or non-therapeutically. Common cellular targets and mechanisms will be sought to elucidate drug interaction pathways. As drug abusers usually use more than one drug, the studies also have public health relevance. Because chemokine receptors are co- receptors for HIV, the studies of how opioids and cannabinoids affect levels and function of chemokine receptors have implications for the effects of drugs of abuse, particularly when taken in combination, on HIV progression.